Recently, Beretta and colleagues [1] reported a protective association of the serotonin 5-HT2A receptor gene polymorphism His452Tyr (C+1354T, rs6314) with systemic sclerosis (SSc) in an Italian population. 5HT2A accounts for most vasoconstrictive and platelet aggregation due to serotonin activity [2]. Beretta and colleagues also demonstrated that plasma from healthy heterozygous carriers of His452Tyr showed decreased platelet aggregation after serotonin stimulus compared to plasma from healthy individuals homozygous for His452. In consequence, they suggested a functional role of His452Tyr in reducing susceptibility to SSc. We performed a population-based replication study in an independent and larger German Caucasian SSc cohort, approved by local ethics committees. DNA was purified from blood samples after obtaining written informed consent. Patients were included according to the German Network for Systemic Scleroderma guidelines [3]. The patient cohort was characterised as follows [4]: all fulfilled minimal requirements of LeRoy and colleagues [5] and 81% fulfilled ACR criteria [6]; 80% were females, 50% presented with the limited cutaneous form (lSSc [3]), 33% with the diffuse cutaneous form (dSSc [3]), 89% carried antinuclear antibodies (ANA-positive), 43% anticentromere antibodies (ACA-positive), 39% antitopoisomerase I antibodies (ATA-positive), and they had a mean age of disease onset of 49.5 ± 13.8 years. Mass spectrometry-based genotyping was applied as described, with minor modifications [4]. Power was >96% to replicate the allelic association and >99% to replicate a decreased minor allele frequency within cases [7], as reported for the Italian population. HapMap data reveal considerable variation of Tyr452 frequency among populations. It is especially high within Africans, emphasizing the importance of appropriate case-control matching. The frequency in our controls was very similar to that in the Caucasian HapMap cohort (0.065 versus 0.063, respectively). It was higher in the Italian population (0.124). We did not find a protective association of His452Tyr with SSc. In contrast, the frequency of Tyr452 was not decreased, but even increased in all SSc patients (Table (Table1).1). Also, no association was found when SSc subgroups stratified for the fulfilment of ACR-criteria, clinical classification (lSSc, dSSc), autoantibody status (ANA-, ACA-, ATA-positive) or sex were compared to healthy donors. However, Tyr452-positive SSc patients were less frequently dSSc positive than His452 homozygous SSc patients (P = 0.048, 9% versus 20%, respectively). This might indicate that the 5HT2A polymorphism may influence the severity of SSc. Table 1 Distribution of C+1354T within German systemic sclerosis patients and controls In summary, we could not replicate an association of the 5HT2A His452Tyr polymorphism with SSc in a larger German Caucasian cohort. However, an influence of this single nucleotide polymorphism on severity of SSc may exist.